LubriTose™

Self Lubricating Excipients

Shifting paradigms in tablet manufacturing

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 Simplifying the Tabletting Process
Direct compression was developed in the mid-1960s to simplify the costly and complex wet or dry granulation methods of
tabletting. In the direct compression method of tablet production, dry ingredients are thoroughly mixed and then compressed
into tablets. This eliminates the wetting and drying steps associated with the wet granulation method. Wet granulations are also
costly because the additional steps require more equipment, and also increased costs for labor, validations and testing, and energy.
As a result, direct compression is a quicker, more economical method that is widely used in the production of high quality tablets.
However, with direct compression and also wet granulation, a lubricant is added in the last blending step to prevent tablets from
sticking to the tablet press tooling. Without the lubrication step, tablets would stick leading to defects such as capping or picking.

LubriTose™ simplifies the tabletting process even further by eliminating the need for adding a separate lubricant to a formulation.
The lubricant is co-processed onto the compression aid, eliminating the need for a separate lubrication blending step.

Wet Granulation Direct Direct Compression

Compression with LubritoseTM
Ô Ô Ô
Kneader High Speed Mixer Fluid Bed Granulator Ô Ô
Ô Ô Ô
Blend Ingredients Blend Ingredients
Dry Mixing Kneader Dry Mix Dry Mix including API including API
Ô Ô Ô
Binder Solution Binder Solution Binder Solution
Ô Ô Ô
Wet Mixing Wet Mixing Spray Granulation
Ô Ô
Ô
Coarse Wet Screening Coarse Wet Screening
Ô
Ô Ô
Granule Drying Granule Drying Drying in Fluid Bed
Ô
Sieving Dry Granule
Ô
Blend in Lubricant
Ô
Tableting Press

Self Lubricating Excipients

The LubriTose™ line of excipients are integrated co-processed systems designed for direct compression, high speed tabletting
operations. Co-processing the directly compressible binding agent with a lubricant enhances the performance of the individual
components while eliminating the limitations typically encountered with using Magnesium Stearate as a lubricant. The ingredients
and the co-processing process were selected to create optimized performance characteristics, such as product flow, lubricity, and
final formulation tablet uniformity compared to physical traditional blend of an excipient and lubricant.

LubriTose™ is available as Anhydrous Lactose, Spray Dried Lactose, Microcrystalline Cellulose (MCC) , or mannitol as a ‘base’ excipient.

2 LubriToseTM
 CO-PROCESSED INGREDIENTS – T YPICAL LEVELS

Lactose NF/EP/JP (96%) Mannitol NF/EP/JP (96%) Microcrystalline Cellulose NF/EP/JP (98%)
Glyceryl Monostearate NF (4%) Glyceryl Monostearate NF (4%) Glyceryl Monostearate NF (2%)

Note: There is not a monoglyceride monograph for EP/JP

Advantages
• Less processing steps
• Eliminates need for external lubricant and time sensitive blending
• Improve flow & tablet weight uniformity
• No impact on compression or API dissolution

LubriTose™ LubriTose™ MCC

LubriTose™ (lactose) Anhydrous Lactose LubriTose™ (MCC) Microcrystalline Cellulose

LubriTose™ has less rounder, smoother particles and less fines due to the agglomeration which equates to less dusting and better flow

LubriTose™ Application Data

In recent years, excipinet manufacturer and equipment manufacturers alike, have tried to find ways to eliminate the need to add
external lubricants to the powder blend, prior to tabletting. The problems of using Mg St as a lubricant are well documented.
However, by combining an alternaitve lubircant (GMS) intimately in to a ‘base’ excipient from the very beginning, we have been
able to develop directly compressible excipients, that are essentially self-lubricating. Along with that, we found additional benefits
were also apparent such as improved flow, and less tablet weight variation, even at high turret speeds.

The LubriTose™ co-processed excipients have been developed to assist formulators with achieving more consistent performance
and delivery characteristics, while meeting the industry challenges for faster, more consistent production. LubriTose combines a
lubricant with a compression aid, allowing for the blending of the API, followed by tabletting, and does not require external
lubrication at the end of the blending process. There are four grades of LubriTose™ products which are based on one of the following
widely used compression aids, Anhydrous Lactose, Spray Dried Lactose, Microcrystalline Cellulose, and Mannitol, all of which are
co-processed with Glyceryl Monostearate as the lubricant. The lubricant is co-processed in a manner that allows for a thin coat of
lubricant over the particles that allows for sufficient lubrication, even after addition of the API.

Testing substantiated that using LubriTose™ versus the traditional blend of an excipient and lubricant provides:

• Substantial benefit in flowability

• Similar lubricity properties without time sensitive overblending
• Improved content uniformity at high speeds

While we looked at model comparisons, API’s can have a major impact on the type of product and how the product can be used.
Our application experts will collaborate with you to develop a customized formulation for your specific needs.

Note: coating adhesion studies have been performed on LubriTose™ tablets and adhesion is not compromised.

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 Improved Powder Flow
LubriTose™ has a lower angle of repose than the excipient/lubricant blend equating to better flowability. LubriTose™ products
have a lower Carr’s Index value than the excipient/lubricant blend. The values were less than 20, which ndicates good flowability.

PRODUCT ANGLE OF REPOSE CARR’S INDEX

LubriTose™ (lactose) 41 17.3

Lactose/Lubricant blend 45 22.2

LubriTose™ MCC 42 18.5

MCC/Lubricant blend 50 23.8

LubriTose™ (mannitol) 34 16

Mannitol/Lubricant blend 36 16.8

Better Flowability
Lower amount of ‘fines’ (below 20 microns) equals less dusting and higher flowability

Differential Volume
6

5.5

4.5
LubriToseTM
4
Volume (%)

Excipient/Lubricant
3.5
blend
3
2.5
Carr’s Index = (tap density-bulk density)/tapped density x100%
2 Excipient/Lubricant blend contains the base excipient and
1.5 0.5% magnesium stearate blended for 5 minutes

0.5

0.4 0.6 1 2 4 6 8 10 20 40 60 100 200 400 600 1000 2000

Particle Diameter (µm)

Tablet weight uniformity at increased press speed

Due to the improvement in flowability of LubriTose™ formulations compared to the excipient/lubricant blend, these formulations
should be optimal for operating at high tablet press speeds. LubriTose™ was compared to an excipient/lubricant blend once again but
at increasing press speeds. The testing was completed at press speeds of 25, 50, and 75 rpm’s. At each speed, ten random tablets were
collected, weighed, and the average calculated. No adjustments were made to the fill weight as the speed was increased. As observed
in the below figure, LubriTose™, show minimal weight variation across various tablet speeds, which is indicative of a very uniform
excipient blend that enables even and consistent flow. With the excipient/lubricant blend, the decrease in average tablet weight was
more pronounced. The tablet press fill weights could be adjusted, but as observed, only minor adjustments would be necessary with
the LubriTose™ formulations. This may result in a more robust process where adjustment may not even be necessary.

4 LubriToseTM
 Improved tablet weight uniformity across various press speeds
0.3 • Optimal for operating at
0.295
high tablet press speeds
.29
25 rpms
.285
50 rpms
• Minimal weight variation
.28
75 rpms across various tablet speeds
.275

.27 • A very uniform excipient

.265
blend that enables even and
.26

.255
consistent flow.
.25
LubriToseTM Excipient/Lubricant Blend
Excipient/lubricant blend contains 0.5% magnesium stearate blended for 5 minutes

Improved Flowability for model API

The flow properties of formulations using LubriTose™ were compared to excipient/lubricant blends. APIs were used in these formulas
and blended with either LubriTose™ or a blend of compression aid and magnesium stearate. For all formulas tested, the flowability
was better (Carr’s index was lower) in the LubriTose™ versions. There was also a large improvement in the LubriTose™ MCC formulas
compared to the excipient/lubricant blends.

A P I P E R C E N TA G E CARR’S

LubriTose™ (lactose) 15.9

lactose/lubricant blend 22.9
Ibuprofen 80
LubriTose™ (MCC) 27.0
MCC/lubricant blend 36.3
LubriTose™ MCC 22.2
Metformin hydrochloride 40
MCC/lubricant blend 40.8
LubriTose™ (lactose) 29.4
lactose/lubricant blend 31.9
Baicalein 20
LubriTose™ MCC 27.8
MCC/lubricant blend 42.6
LubriTose™ (lactose) 20.9
lactose/lubricant blend 23.4
Aspirin 50
LubriTose™ MCC 25.1
MCC/lubricant blend 40.2
LubriTose™ (lactose) 23.0
lactose/lubricant blend 25.8
Vitamin C 40
LubriTose™ MCC 24.1
MCC/lubricant blend 43.4
LubriTose™ (lactose) 32.4
lactose/lubricant blend 28.4
Mefenamic Acid 50
LubriTose™ MCC 27.6
MCC/lubricant blend 31.9
Notes: Carr’s Index =
LubriTose™ (lactose) 22.4
(tap density-bulk density)/tapped density x 100%.
lactose/lubricant blend 23.0 Excipient/lubricant blend contains
Piroxicam 60
LubriTose™ MCC 27.4 0.5% Magnesium Stearate blended for
MCC/lubricant blend 47.0 5 minutes.

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 No Effect in Lubricity & Compression
LubriTose™ demonstrates no effect on lubricity and compressibility. The ejection force of tablets made with LubriTose™ were
compared to tablets made with an excipient/lubricant blend. The lubricity of LubriTose is equivalent to the formulas where
Magnesium Stearate is used at all press speeds tested. Also as demonstrated, LubriTose™ will not lose compressibility and there
is no reduction in tablet hardness.

200
180
160
API+Excipient/Lubricant Blend, 15rpm
140
Ejection Force (N)

API+LubriToseTM, 15rpm
120
API+Excipient/Lubricant Blend, 25rpm
100
API+LubriToseTM, 25rpm
80
API+Excipient/Lubricant Blend, 35rpm
60
API+LubriToseTM, 35rpm
40
20
0
5 6 7 8 9 10 11 12 13

Compression Force (kN)

Notes: API (Ibuprofen) load was 60% of formula. Excipient/Lubricant blend contained 1.0%
Magnesium Stearate and was blended for 5 minutes.

LubriToseTM Compressibility
60

50
Tablet Hardness (N)

40
• Lubricity maintained
30
• No loss of compressibility
20

10 • Tablet hardness is not compromised

0
400 600 800 1000 1200 1400 1600

Compression Force (lbs)

LubriToseTM Excipient/Lubricant Blend

Notes: Excipient/Lubricant blend contains 0.5% magnesium stearate. Blending Time: 5 minutes

Lactose/Mg. Stearate – Compression vs Hardness LubriToseTM Compression vs Hardness

70 70
Tablet Hardness (N)

Tablet Hardness (N)

60 60
50 50
40 40
30 30
20 20
10 10
0 0
400 600 800 1000 1200 1400 500 700 900 1100 1300 1500

Compression Force (lbs) Compression Force (lbs)

Blended for 2 minutes Blended for 30 minutes Blended for 2 minutes Blended for 60 minutes

6 LubriToseTM
 Minimal Usage Levels
LubriTose™ was tested by adding Acetaminophen to the product at increasing levels to observe ejection force and the point
at which sticking or capping occurs. No sticking or capping was observed when using the recommended usage level of 25%
LubriTose in the formula. Also, the ejection force decreased at increasing compression forces, meaning presses can be run at
higher forces with less wear.

LubriToseTM Compression vs Hardness

88
86
84 • Minimum recommended usage
Tablet Hardness (N)

82 is approximately 25%
80
78 • Even at lower use levels, adequate
76
lubrications is observed
74
72
70
450 650 850 1050 1250 1450

Compression Force (lbs)

100% LubriToseTM 75% LubriToseTM 25% Acetaminophen

50% LubriToseTM 50% Acetaminophen 25% LubriToseTM 75% Acetaminophen

No Impact on Dissolution with some APIs

The table below represents the dissolution of poorly soluble drugs with LubriTose™ compared to the excipient/lubricant blend.
In the Lactose products, 5% Croscarmellose was added. Overall dissolution remained consistent when using LubriTose™. In some
cases, a faster dissolution was observed. This may be due to the fact that since the disintegrant is added after the lubricant, it does
not get coated over by the lubricant.

• Overall dissolution is not affected

• In some cases, a faster dissolution is observed

DISSOLUTION (%)

Mefenamic acid Piroxicam Simvastatin Ibuprofen Baicalein Puerarin Breviscapine

LubriTose™ ANa 75.2 100.4 103.7 90.9 62.7 96.5 80.2

Excipient/Lubricant blend 70.9 103.7 102.9 92.7 45.2 96.4 62.1

LubriTose™ MCCb Not done 89.4 102.2 90.5 67.0 54.3 66.5

Excipient/Lubricant blend Not done 97.0 102.0 107.0 57.2 51.7 59.5

Notes: ‘a’ represents the addition of 5% of disintegrants; ‘b’ represents with no disintegrants. The excipient/lubricant blend contains 0.5% Magnesium
Stearate blended for 5 minutes. Dissolution performed according to appropriate Pharmacopeia and recorded as % measured at listed monograph time.

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460 - Distrito Industrial
Please note that the information herein is believed to be accurate and Cep - 13054-750
complete. However, no warranty or guarantee whatsoever is made or is to Campinas, Sao Paulo
be implied with respect to such information or with respect to any other
Brazil
product, method, performance or apparatus referred herein. Nothing herein
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shall be construed as a recommendation to use, manufacture, sell or act in
violation of any intellectual property rights or legal requirements. Sheffield Fax: +55-19-3765-5108
Bio-Science is a trademark of Kerry Group.
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MC/LubriToseEng/062015